Lett Tristram A, Walter Henrik, Brandl Eva J
Department of Psychiatry and Psychotherapy, Campus Mitte, Charité Universitätsmedizin Berlin, Berlin, Germany.
Psychiatrische Universitätsklinik der Charité im St. Hedwig-Krankenhaus, Große Hamburger Straße 5-11, 10115, Berlin, Germany.
CNS Drugs. 2016 Dec;30(12):1169-1189. doi: 10.1007/s40263-016-0385-9.
Genetic variation underlies both the response to antidepressant treatment and the occurrence of side effects. Over the past two decades, a number of pharmacogenetic variants, among these the SCL6A4, BDNF, FKBP5, GNB3, GRIK4, and ABCB1 genes, have come to the forefront in this regard. However, small effects sizes, mixed results in independent samples, and conflicting meta-analyses results led to inherent difficulties in the field of pharmacogenetics translating these findings into clinical practice. Nearly all antidepressant pharmacogenetic variants have potentially pleiotropic effects in which they are associated with major depressive disorder, intermediate phenotypes involved in emotional processes, and brain areas affected by antidepressant treatment. The purpose of this article is to provide a comprehensive review of the advances made in the field of pharmacogenetics of antidepressant efficacy and side effects, imaging findings of antidepressant response, and the latest results in the expanding field of imaging-pharmacogenetics studies. We suggest there is mounting evidence that genetic factors exert their impact on treatment response by influencing brain structural and functional changes during antidepressant treatment, and combining neuroimaging and genetic methods may be a more powerful way to detect biological mechanisms of response than either method alone. The most promising imaging-pharmacogenetics findings exist for the SCL6A4 gene, with converging associations with antidepressant response, frontolimbic predictors of affective symptoms, and normalization of frontolimbic activity following antidepressant treatment. More research is required before imaging-pharmacogenetics informed personalized medicine can be applied to antidepressant treatment; nevertheless, inroads have been made towards assessing genetic and neuroanatomical liability and potential clinical application.
基因变异是对抗抑郁治疗产生反应以及出现副作用的基础。在过去二十年中，一些药物遗传学变异，包括血清素转运体基因（SCL6A4）、脑源性神经营养因子（BDNF）、FK506结合蛋白5（FKBP5）、鸟嘌呤核苷酸结合蛋白（G蛋白）β3亚基（GNB3）、谷氨酸受体离子型红藻氨酸4（GRIK4）和ATP结合盒转运体B1（ABCB1）基因等，在这方面受到了关注。然而，效应量小、独立样本结果不一以及荟萃分析结果相互矛盾，导致药物遗传学领域在将这些发现转化为临床实践时存在固有困难。几乎所有抗抑郁药物遗传学变异都具有潜在的多效性，它们与重度抑郁症、情绪过程中涉及的中间表型以及受抗抑郁治疗影响的脑区相关。本文旨在全面综述抗抑郁疗效和副作用的药物遗传学领域取得的进展、抗抑郁反应的影像学发现以及影像药物遗传学研究不断扩展领域的最新成果。我们认为，越来越多的证据表明，遗传因素通过影响抗抑郁治疗期间的脑结构和功能变化来对治疗反应产生影响，并且将神经影像学和基因方法相结合可能比单独使用任何一种方法更有效地检测反应的生物学机制。血清素转运体基因（SCL6A4）在影像药物遗传学方面的发现最具前景，它与抗抑郁反应、情感症状的额边缘预测因子以及抗抑郁治疗后额边缘活动的正常化存在趋同关联。在影像药物遗传学指导下的个性化医学能够应用于抗抑郁治疗之前，还需要进行更多研究；尽管如此，在评估遗传和神经解剖易感性以及潜在临床应用方面已经取得了进展。
